We propose to examine the relationship between substrate oxidation, lipotoxicity and proximal tubule cell death. We have shown that activation of PPAR using a ligand, or by increased expression of PPAR in the proximal tubule using transgenic mice ameliorates kidney function in the ischemia reperfusion injury (IRI), and cisplatin model of nephrotoxicity. Our preliminary studies demonstrate a significant reduction in proximal tubule cell death and reduced interstitial fibrosis in PPAR Tg mice subjected to both unilateral ischemia and Unilateral Ureteral Obstruction (UUO), when compared to wild type mice. Our central hypothesis predicts that increased expression and activity of proximal tubule and pericyte PPAR interdict tubulo-interstitial inflammation and renal fibrosis, a hallmark of the progression from Acute to Chronic Kidney Disease (CKD). Specific Aim 1 is to determine whether increased proximal tubule (PT)-PPAR interferes with tubulo-interstitial fibrosis. We hypothesize that increased expression of proximal tubule PPAR attenuates renal fibrosis. We will use wild type, genetically deficient PPAR mice, and PPAR transgenic mice and two animal models of renal fibrosis to determine if increased fatty acid oxidation, lipoprotein lipase activity, and increased autophagy contribute to reduced lipotoxicity and prevent proximal tubule cell death in models of renal fibrosis. Specific Aim 2 is to determine cellular mechanisms by which pericyte PPAR influences pericyte to myofibroblast transition. We propose to isolate and culture mouse kidney pericytes in order to 1) determine the effects of PPAR overexpression on the pericyte-to-myofibroblast transition, 2) determine whether the PPAR-mediated increase in fatty acid oxidation, reduced neutral lipid accumulation, and/or changes to pericyte adipogenesis prevent the pericyte conversion to myofibroblasts in vitro, and 3) to determine the role of PPAR deficiency on the transition of pericytes to myofibroblasts. Altogether, these studies will further advance our knowledge of pericyte metabolism and function, which should provide additional therapeutic targets to prevent the progression of AKI to CKD.